Serotypes and Clonal Composition of Streptococcus pneumoniae Isolates Causing IPD in Children and Adults in Catalonia before 2013 to 2015 and after 2017 to 2019 Systematic Introduction of PCV13.

The goal of this study was to investigate the distribution of serotypes and clonal composition of Streptococcus pneumoniae isolates causing invasive pneumococcal disease (IPD) in Catalonia, before and after systematic introduction of PCV13. Pneumococcal strains isolated from normally sterile sites obtained from patients of all ages with IPD received between 2013 and 2019 from 25 health centers of Catalonia were included. Two study periods were defined: presystematic vaccination period (2013 and 2015) and systematic vaccination period (SVP) (2017 to 2019). A total of 2,303 isolates were analyzed. In the SVP, there was a significant decrease in the incidence of IPD cases in children 5 to 17 years old (relative risk [RR] 0.61; 95% confidence interval [CI] 0.38 to 0.99), while there was a significant increase in the incidence of IPD cases in 18- to 64-year-old adults (RR 1.33; 95% CI 1.16 to 1.52) and adults over 65 years old (RR 1.23; 95% CI 1.09 to 1.38). Serotype 8 was the major emerging serotype in all age groups except in 5- to 17-year-old children. In children younger than 5 years old, the main serotypes in SVP were 24F, 15A, and 3, while in adults older than 65 years they were serotypes 3, 8, and 12F. A significant decrease in the proportions of clonal complexes CC156, CC191, and ST306 and an increase in those of CC180, CC53, and CC404 were observed. A steady decrease in the incidence of IPD caused by PCV13 serotypes indicates the importance and impact of systematic vaccination. The increase of non-PCV13 serotypes highlights the need to expand serotype coverage in future vaccines and rethink vaccination programs for older adults. IMPORTANCE We found that with the incorporation of the PCV13 vaccine, the numbers of IPD cases caused by serotypes included in this vaccine decreased in all of the age groups. Still, there was an unforeseen increase of the serotypes not included in this vaccine causing IPD, especially in the >65-year-old group. Moreover, a significant increase of serotype 3 included in the vaccine has been observed; this event has been reported by other researchers. These facts call for the incorporation of more serotypes in future vaccines and a more thorough surveillance of the dynamics of this microorganism.

[Utilization study in real clinical practice of ceftolozane/tazobactam vs aminoglycosides and/or colistin in the treatment of multirresistant or extremely resistant Pseudomonas aeruginosa]. / Estudio de utilización en práctica clínica real de ceftolozano/tazobactam frente a aminoglucósidos y/o colistina en el tratamiento de Pseudomonas aeruginosa.

OBJECTIVE: Comparative "real life" data on the effectiveness and safety of ceftolozane/tazobactam (C/T) versus other regimens (aminoglycosides/colistin/combination), in the treatment of multi-resistant (MDR) and extremely resistant (XDR) Pseudomonas aeruginosa (PA), are needed to establish positions. METHODS: Observational, retrospective study of patients with microbiological confirmation of MDR and XDR PA from July 2016 up to December 2018 in a tertiary hospital. Variables: age, sex, comorbidities, risk factors for multidrug resistance, variables related to infection, source of infection, microorganism and type of sample, antibiotic treatment, clinical cure, microbiological cure, recurrence, mortality on admission and 30 days post-discharge. Patients were classified according to received antibiotic treatment, C/T or aminoglycosides/colistin/combination. RESULTS: A total of 405 patients with PA MDR and XDR infection (73.1% men, mean age 63 ± 15 years) were studied. An 87.1% of PA XDR and a 12.9% MDR were observed. All patients received C/T as targeted therapy and in the aminoglycosides/colistin/combination group were 73.5%. Patients in the C/T group present worse prognostic factors: septic shock (30.0%) and catheterization (90.0%) (p<0.05). There were not statistically significant differences in microbiological cure (p=0.412), recurrence (p=0.880) and clinical cure (p=0.566). There were not statistically significant differences in mortality at admission (p=0.352) or at 30 days after discharge (p=0.231). A 17.2% of the patients with aminoglycosides/colistin/combination had acute kidney injury according to RIFLE criteria and 4.3% with C/T. CONCLUSIONS: The data obtained suggest that there have been no differences in effectiveness (clinical or microbiological cure) in favour of C/T, although, in the period studied, it was used in most cases in multitreated patients with a worse prognosis. Randomized and prospective studies would be needed to establish an adequate positioning.

Outcomes of the PIRASOA programme, an antimicrobial stewardship programme implemented in hospitals of the Public Health System of Andalusia, Spain: an ecologic study of time-trend analysis.

OBJECTIVES: Inappropriate antimicrobial use favours the spread of resistance, and multidrug-resistant microorganisms (MDR) are currently of major concern. Antimicrobial stewardship programmes (ASPs) are essential for improving antibiotic use in hospitals. However, their impact on entire healthcare systems has not been thoroughly assessed. Our objective was to provide the results of an institutionally supported ASP involving 31 public hospitals in Andalusia, Spain. METHODS: We designed an ecologic time-series study from 1 January 2014 to 31 December 2017. Quarterly, data on indicators were collected prospectively, and feedback reports were provided. PIRASOA is an ongoing clinically based quality-improvement programme whose key intervention is the educational interview, regular peer-to-peer interventions between advisors and prescribers to reinforce the appropriate use of antibiotics. Seventy-two indicators were monitored to measure prescribing quality (inappropriate treatments), antimicrobial consumption (defined daily doses per 1000 occupied bed-days), incidence density of MDR per 1000 occupied bed-days and crude mortality rate associated with bloodstream infections. We used Joinpoint regression software to analyse the trends. RESULTS: The quality of antimicrobial prescribing improved markedly, and the inappropriate treatment rate was significantly lower, with quarterly percentage change (QPC) = -3.0%, p < 0.001. Total antimicrobial consumption decreased (QPC = -0.9%, p < 0.001), specifically carbapenems, amoxicillin/clavulanic acid, quinolones and antifungal agents, whereas antipseudomonal cephalosporin use increased. While the incidence of MDR showed a sustained decreasing trend (QPC = -1.8%; p 0.002), the mortality of patients with bloodstream infections remained stable (QPC = -0.2%, p 0.605). CONCLUSIONS: To date, the PIRASOA programme has succeeded in optimizing the use of antimicrobial agents and has had a positive ecologic result on bacterial resistance at level of an entire healthcare system.

Cannabis resin in the region of Madrid: Adulteration and contamination.

The aim of this study is to analyze the adulteration and contamination of cannabis resin obtained on the streets of Madrid, in order to establish whether it is suitable for human consumption. A total of 90 samples obtained through street vending in the Region of Madrid (CAM) were analyzed. Our results showed a direct relationship between the shape of the samples (acorn or ingot) and the presence of foreign elements, adulterants and microbiological contamination. Foreign elements were found in 64.7% of the ingot-shaped samples and in 30.2% of the acorn-shaped samples (p < 0.01); 25% of the samples were deliberately adulterated, 66.7% of which had an ingot shape. With regard to microbiological contamination, 93% of acorns were contaminated by E. coli, compared to 29.4% of ingots (p < 0.0001). In addition, all samples with fecal odor were acorns and were contaminated by E. coli. Ten per cent of the samples were contaminated by Aspergillus; of these, 66.7% had the shape of an acorn. Overall, our results showed that most (88.3%) of the hashish samples were not suitable for consumption. This percentage was significantly higher (p < 0.0001) in acorn than in ingot samples (100% vs. 58.8%). Hence, illegal street vending of hashish constitutes a public health issue.

Política de antibióticos. Comisión de Infecciones y uso de antimicrobianos / The antibiotic policy. The Infection Committee and antimicrobial use

La política de antibióticos es el conjunto de estrategias y actividades llevadas a cabo para organizar el tratamiento antimicrobiano en el hospital, y conseguir resultados en salud para los pacientes. Los principios básicos que deben dirigirla son la medicina basada en la evidencia, la epidemiología local y la libertad de prescripción de los facultativos. En la actualidad, la política de antibióticos es más necesaria que nunca por razones clínicas, epidemiológicas y económicas. La Comisión de Infecciones es la responsable de la política de antibióticos en los hospitales. Sus funciones, como órgano asesor de la dirección médica, son el análisis de la epidemiología de las infecciones del centro, las medidas para su prevención y control, la mejora del uso apropiado de los antimicrobianos, la formación y la producción de conocimientos. Conseguir los objetivos clínicos, ecológicos y económicos de la política de antibióticos no es tarea fácil. Poner de acuerdo a cientos de profesionales en torno a las recomendaciones sobre indicaciones, posología y duración del tratamiento antibiótico basadas en las mejores evidencias científicas y en las guías locales, es complejo, pero se puede hacer. Para ello es clave que la Comisión de Infecciones desarrolle el PROA a través de un equipo multidisciplinar y con liderazgo profesional, y que cuente con el apoyo institucional que asegure que el buen uso de los antimicrobianos es un objetivo prioritario del centro, y por lo tanto de cada uno de los servicios implicados, y que el equipo de PROA dispone de los recursos necesarios (AU)

The antibiotic policy is the set of strategies and activities undertaken to organize the antimicrobial treatment in the hospital, and achieve health outcomes for patients. The basic principles are to be direct evidence-based medicine, local epidemiology and freedom for prescribing physicians. Anantibiotic policy is now more necessary than ever for clinical, epidemiological and economic reasons. The Infection Committee is responsible for the antibiotics policy in hospitals. Its functions as an advisory body to the medical directorate are the analysis of the epidemiology of the infections in the center, measures for its prevention and control, improving the appropriate use of antimicrobials, training, and knowledge production. To achieve clinical, environmental and economic policy objectives of antibiotics is not easy. The agreement of hundreds of professionals for recommendations on indications, dosage and duration of antibiotic treatment, based on the best scientific evidence and local guides is complex, but it can be done. The key to this is that the Infection Committee develops antimicrobial stewardship through a multidisciplinary team and professional leadership, and has the institutional support to ensure that the proper use of antimicrobials is a priority for the center, and therefore of each of the services involved, and that the team has the resources for antimicrobial stewardship (AU)

[The antibiotic policy. The Infection Committee and antimicrobial use]. / Política de antibióticos. Comisión de Infecciones y uso de antimicrobianos.

The antibiotic policy is the set of strategies and activities undertaken to organize the antimicrobial treatment in the hospital, and achieve health outcomes for patients. The basic principles are to be direct evidence-based medicine, local epidemiology and freedom for prescribing physicians. An antibiotic policy is now more necessary than ever for clinical, epidemiological and economic reasons. The Infection Committee is responsible for the antibiotics policy in hospitals. Its functions as an advisory body to the medical directorate are the analysis of the epidemiology of the infections in the center, measures for its prevention and control, improving the appropriate use of antimicrobials, training, and knowledge production. To achieve clinical, environmental and economic policy objectives of antibiotics is not easy. The agreement of hundreds of professionals for recommendations on indications, dosage and duration of antibiotic treatment, based on the best scientific evidence and local guides is complex, but it can be done. The key to this is that the Infection Committee develops antimicrobial stewardship through a multidisciplinary team and professional leadership, and has the institutional support to ensure that the proper use of antimicrobials is a priority for the center, and therefore of each of the services involved, and that the team has the resources for antimicrobial stewardship.

[Off-label approval of drug use in a tertiary hospital]. / Autorización de usos de medicamentos fuera de indicación en un hospital de tercer nivel.

BACKGROUND AND OBJECTIVE: The Pharmacy and Therapeutics Committee (PTC) evaluates the requests for off-label uses with an abbreviated report format. The aim of this study is to perform a descriptive analysis of this activity and to study the rate of approvals. MATERIAL AND METHODS: A descriptive study was performed on the PTC reports in a tertiary hospital between September 2009 and April 2011. The type of drug by treatment group and by type of dispensing, indication and requesting department was analysed. The final decision adopted was studied as the primary outcome, and the percentage of requests approved according to the characteristics of the drug evaluated, indication requested, alternatives used, evidence and cost, as secondary outcomes. RESULTS: A total of 51 applications were analysed, of which 60.8% were drugs for hospital use and 54.9% cytostatic. The most requested indications were the onco-haematological (43.2%) and autoimmune (35.3%). Haematology was the department that made most requests (11 requests with 72.7% approved), Oncology and Paediatrics (both with 10 requests, with 50% approved). Almost two-thirds (60.8%) of the requests were approved. Of those that were not approved, 11 had not used up the therapeutic alternatives, and 8 had no evidence. Just under half (47.1%) of the drugs requested had a cost/patient between 10,000-100,000 euros,of which 58.3% were approved (cost per course of treatment if it had a defined period, or cost of treatment per year for chronic treatment). CONCLUSION: There is an increase in the activity of the PTC that is growing over the years. Most applications focus on drugs for hospital use and cytostatic drugs by Onco-haematology. There is a high rate of approval by the PTC, and high variability in the percentage of approval depending on the department and the evidence of use. The difference between approved and unapproved requests followed a logic of cost-effectiveness.

When neighbourhood matters: tumour microenvironment.

Tumour development comprises a complex succession of events that prompt incipient cancer cells to proliferate out of control and to acquire migratory and invasive capabilities. Over the past decades, cancer research has produced a wealth of knowledge about the intrinsic alterations of neoplastic cells within tumours. However, tumours now have come to be understood to function as complex tissues in which numerous cells, collectively termed the tumour microenvironment, play a critical role. These include inflammatory cells, blood vessels, fibroblasts and changes in their secreted extracellular matrix. This is revealing additional mechanisms of tumorigenesis that has spawned a new era of therapeutic strategies aimed at eradicating tumours.

When neighbourhood matters: tumour microenvironment

Tumour development comprises a complex succession of events that prompt incipient cancer cells to proliferate out of control and to acquire migratory and invasive capabilities. Over the past decades, cancer research has produced a wealth of knowledge about the intrinsic alterations of neoplastic cells within tumours. However, tumours now have come to be understood to function as complex tissues in which numerous cells, collectively termed the tumour microenvironment, play a critical role. These include inflammatory cells, blood vessels, fibroblasts and changes in their secreted extracellular matrix. This is revealing additional mechanisms of tumorigenesis that has spawned a new era of therapeutic strategies aimed at eradicating tumours (AU)

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Mechanisms of reduced susceptibility to amoxycillin-clavulanic acid in Escherichia coli strains from the health region of Tortosa (Catalonia, Spain).

This study investigated the mechanisms involved in reduced susceptibility to amoxycillin-clavulanic acid and the prevalence of enzymes compatible with inhibitor-resistant TEM (IRT) beta-lactamases produced by Escherichia coli isolates from patients in north-eastern Spain. The resistance mechanisms of 158 strains showing resistance or intermediate resistance to amoxycillin-clavulanic acid among 1122 ampicillin-resistant clinical isolates of E. coli were assessed on the basis of their beta-lactam resistance phenotypes. beta-Lactamases produced by strains showing resistant phenotypes suggestive of inhibitor-resistant penicillinase production were characterised by their isoelectric point. Specific activity and the concentration of clavulanic acid required to inhibit beta-lactamase activity by 50% (IC50) were determined in strains harbouring enzymes that focused at pI 5.2 or 5.4 in order to achieve presumptive identification of IRT beta-lactamases. Resistance phenotypes were consistent with overproduction of TEM-1, TEM-2 or SHV-1 beta-lactamases in 56 strains, with AmpC cephalosporinase hyperproduction in 46 strains, and with production of inhibitor-resistant penicillinases in 49 strains. Of the latter isolates, 17 produced moderately high or high levels of enzymes co-focusing with TEM-1, 17 produced enzymes co-focusing with OXA-1 (n = 12) or with PSE-1 (n = 5), either alone or in association with TEM-1, while only 15 produced enzymes with a phenotype characteristic of IRT beta-lactamases. It was concluded that resistance to amoxycillin-clavulanic acid in E. coli isolates from this area was mainly associated with presumptive overproduction of TEM-1, TEM-2 or SHV-1 beta-lactamases (46%) or of AmpC cephalosporinase (29%), while the occurrence of enzymes categorised as IRT beta-lactamases was unusual (9.5%).

A new role for E12/E47 in the repression of E-cadherin expression and epithelial-mesenchymal transitions.

Down-regulation of E-cadherin expression is a determinant of tumor cell invasiveness, an event frequently associated with epithelial-mesenchymal transitions. Here we show that the mouse E12/E47 basic helix-loop-helix transcription factor (the E2A gene product) acts as a repressor of E-cadherin expression and triggers epithelial-mesenchymal transitions. The mouse E47 factor was isolated in a one-hybrid system designed to isolate repressors of the mouse E-cadherin promoter. Epithelial cells ectopically expressing E47 adopt a fibroblastic phenotype and acquire tumorigenic and migratory/invasive properties, concomitant with the suppression of E-cadherin expression. Suppression of E-cadherin expression under stable or inducible expression of E47 in epithelial cells occurs at the transcriptional level and is dependent on the E-boxes of the E-cadherin promoter. Interestingly, analysis of endogenous E2A expression in murine and human cell lines illustrated its presence in E-cadherin-deficient, invasive carcinoma cells but its absence from epithelial cell lines. This expression pattern is consistent with that observed in early mouse embryos, where E2A mRNA is absent from epithelia but strongly expressed in the mesoderm. These results implicate E12/E47 as a repressor of E-cadherin expression during both development and tumor progression and indicate its involvement in the acquisition and/or maintenance of the mesenchymal phenotype.

The transcription factor snail controls epithelial-mesenchymal transitions by repressing E-cadherin expression.

The Snail family of transcription factors has previously been implicated in the differentiation of epithelial cells into mesenchymal cells (epithelial-mesenchymal transitions) during embryonic development. Epithelial-mesenchymal transitions are also determinants of the progression of carcinomas, occurring concomitantly with the cellular acquisition of migratory properties following downregulation of expression of the adhesion protein E-cadherin. Here we show that mouse Snail is a strong repressor of transcription of the E-cadherin gene. Epithelial cells that ectopically express Snail adopt a fibroblastoid phenotype and acquire tumorigenic and invasive properties. Endogenous Snail protein is present in invasive mouse and human carcinoma cell lines and tumours in which E-cadherin expression has been lost. Therefore, the same molecules are used to trigger epithelial-mesenchymal transitions during embryonic development and in tumour progression. Snail may thus be considered as a marker for malignancy, opening up new avenues for the design of specific anti-invasive drugs.

H-Ras activation promotes cytoplasmic accumulation and phosphoinositide 3-OH kinase association of beta-catenin in epidermal keratinocytes.

The mechanisms underlying downregulation of the cadherin/catenin complexes and beta-catenin signaling during tumor progression are not fully understood. We have analyzed the effect of oncogenic H-Ras on E-cadherin/catenin complex formation/stabilization and beta-catenin distribution in epidermal keratinocytes. Microinjection or stable expression of V12Ras into keratinocytes promotes the loss of E-cadherin and alpha-catenin and relocalization of beta-catenin to the cytoplasm and nucleus. Moreover, these effects are dependent on PI3K (phosphoinositide 3-OH kinase) activity. Interestingly, a strong association of p85alpha and p110alpha subunits of PI3K with beta-catenin is induced in V12Ras-expressing keratinocytes, and in vitro binding assays show a direct interaction between beta-catenin and p85alpha. Overexpression of either V12Ras or constitutively active p110alpha induces metabolic stabilization of beta-catenin and promotes its accumulation in cytoplasmic and nuclear pools. In addition, the interaction of beta-catenin with the adenomatous polyposis coli protein is blocked in V12Ras and p110alpha transformants though no changes in glycogen synthase kinase 3 beta activity could be detected. Nevertheless, in V12Ras transformants the in vivo phosphorylation of beta-catenin in Ser residues is strongly decreased. These results indicate that H-Ras activation induces the relocalization and cytoplasmic stabilization of beta-catenin by a mechanism involving its interaction with PI3K.

Vinculin but not alpha-actinin is a target of PKC phosphorylation during junctional assembly induced by calcium.

The establishment of the junctional complex in epithelial cells requires the presence of extracellular calcium, and is controlled by a network of reactions involving G-proteins, phospholipase C and protein kinase C. Since potential candidates for phosphorylation are the tight junction associated proteins ZO1, ZO2 and ZO3, in a previous work we specifically explored these molecules but found no alteration in their phosphorylation pattern. To continue the search for the target of protein kinase C, in the present work we have studied the subcellular distribution and phosphorylation of vinculin and alpha-actinin, two actin binding proteins of the adherent junctions. We found that during the junctional sealing induced by Ca2+, both proteins move towards the cell periphery and, while there is a significant increase in the phosphorylation of vinculin, alpha-actinin remains unchanged. The increased phosphorylation of vinculin is due to changes in phosphoserine and phosphothreonine content and seems to be regulated by protein kinase C, since: (1) DiC8 (a kinase C stimulator) added to monolayers cultured without calcium significantly increases the vinculin phosphorylation level; (2) H7 and calphostin C (both protein kinase C inhibitors) completely abolish this increase during a calcium switch; (3) inhibition of phosphorylation during a calcium switch blocks the subcellular redistribution of vinculin and alpha-actinin. These results therefore suggest that vinculin phosphorylation by protein kinase C is a crucial step in the correct assembly of the epithelial junctional complex.

[Characterization of the resistance to combinations of beta lactams and inhibitors of beta-lactamases in Escherichia coli. Effect of the type and amount of beta-lactamase production]. / Caracterización de la resistencia a asociaciones de betalactámicos e inhibidores de betalactamasas en Escherichia coli. Influencia del tipo y nivel de producción de betalactamasas.

BACKGROUND: The aim of this study was to characterize resistance of Escherichia coli in our environment to four associations of beta-lactams and beta-lactamase inhibitors (beta Lac) studying the influence of the type and level of beta Lac production. METHODS: The minimum inhibitory concentration (MIC) to ampicillin/sulbactam (A/S), amoxycillin/clavulanic acid (A/C), ticarcillin/clavulanic acid (T/C) and piperacillin/tazobactam (P/T) assessed was in 245 strains of E. coli resistant to ampicillin, consecutively isolated in our laboratory from September 1995 to March 1996. The beta Lac produced by these isolates were identified by isoelectrofocusing and spectrophotometrically quantified. RESULTS: The sensitivity to A/S, A/C, T/C and P/T was of 9.4, 86.9, 64.5 and 89.4%, respectively. The strains with only one beta Lac which cofocused with TEM-1 were the most frequent (215/245), followed by those producing a cofocusing enzyme with SHV-1 (7/245). A significant correlation was observed between beta Lact activity of the 215 TEM-1 strains and their MIC at A/S (r = 0.53; p < 0.001), A/C (r = 0.46; p < 0.001), T/TC (r = 0.58; p < 0.001), and P/T (r = 0.42; p < 0.001). The comparison between enzyme activity of the isolates of the different categories of susceptibility showed significant differences (p < 0.05) for the four associations studied. CONCLUSION: TEM-1 production is the main cause of resistance to beta-lactams in E. coli in our environment. The inhibitory efficacy of sulbactam, clavulanic acid and tazobactam over TEM-1 is inversely proportional to the amounts of enzyme produced. The high rate of resistance to A/S and T/C E. coli presents in our environment is mainly due to a hyperproduction of TEM-1.